Amlodipine, the IUPAC Name for 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, is a long-acting calcium channel blocker useful in the treatment of cardiovascular diseases, such as angina pectoris, hypertension, congestive heart failure, etc.
Amlodipine is a chiral compound with a chiral center. In general, pure stereoisomers are known to have better therapeutic effects than racemic mixtures. Furthermore, racemic compounds tend to have different pharmacokinetic profiles, depending on the steric arrangement of the isomer compounds or their salts. There are two possible stereoisomers of amlodipine because it has one chiral center, that is, R-(+)-amlodipine and (S-(−)-amlodipine, which are different from each other in pharmacokinetic profile. The R-(+)-isomer of amlodipine is a potent inhibitor of smooth muscle cell migration despite the fact that it does not exhibit calcium channel-blocking activity (U.S. Pat. No. 6,080,761). So, it is useful for preventing and treating atherosclerosis. On the other hand, the (S)-(−)-isomer of amlodipine is a potent calcium channel blocker. For ideal use as a calcium channel blocker, amlodipine is administered in the form of S-(−)-amlodipine, substantially free of its (+) stereoisomer (U.S. Pat. No. 6,057,344). U.S. Pat. No. 6,291,490 also discloses S-(−)-amlodipine, reporting that S-(−)-amlodipine avoids the adverse effect of amlodipine in racemic mixtures. Therefore, there is a need for a methodology by which chiral compounds such as amlodipine are separated as pure isomers.
Several methods of separating optical amlodipine isomers are known: 1) Resolution of two optical amlodipine isomers by the separation of the resolution of diastereomeric azide ester (represented by the following Formula 1(a)) (J. E. Arrowsmith et al., J. Med. Chem. (1986), 29, 1696], 2) Separation of an intermediate (represented by the following Formula 1(b)) by use of cinchonidine carboxylate (EP 0,331,315), and 3) Chromatographic separation of diastereomeric amide ester (represented by the following Formula 1(c)) (S. Goldman et al., J. Med. Chem. (1992) 35 3341). However, it was noted that these methods are not suitable for industrial application.

(a) R═CH2CH(OCH3)Ph, X═N3,
(b) R═H, X═N3,
(c) R═CH2CH3, X=(1S)-camphanoyl amine.
Recently, a series of techniques having improved industrial applicability has been reported. Most of the techniques feature the formation of diastereomeric salts of amlodipine with D- or L-tartaric acid and subsequent separation with an appropriate solvent. These techniques may be useful because diastereomeric salts of amlodipine can be separated merely by a physical process, and the salts may also be easily detached with a base.
For example, U.S. Pat. No. 6,046,338 and Korean Patent No. 10-0188980 disclose the separation method of enantiomeric isomers of amlodipine from mixtures thereof by reacting the mixture of isomers with either L- or D-tartaric acid in dimethyl sulfoxide (DMSO) for the precipitation of DMSO solvate of D- or L-tartrate. The precipitate is a amlodipine-hemitartrate-DMSO monosolvate composed of 2:1:2 amlodipine:tartrate:DMSO.
U.S. Pat. No. 6,646,131 described a method for the separation of (R)-(+)- and (S)-(−)-isomers of amlodipine through the reaction of the mixture of isomers with D- or L-tartaric acid in deuterium-substituted dimethyl sulfoxide (DMSO-d6)) for the precipitation of a DMSO-d6 solvate of a D- or L-tartrate salt of amlodipine isomers.
Korean Patent Publication No. 10-2004-62575 discloses the separation of optical isomers of amlodipine via the formation of amlodipine-hemitartrate-DMAC monosolvate in dimethylacetate amide (DMAC) and treatment with a base.
However, as described in the patent document, D- and L-tartaric acid are used as optical resolution agents for forming S-(−)- and R-(+)-amlodipine, respectively. Particularly, the methods disclosed in U.S. Pat. No. 6,046,338 and Korean Patent No. 10-0188980 are advantageous in terms of the high yield and optical purity of amlodipine enantiomers, but are disadvantageous in terms of economy because D-tartaric acid, serving as an optical resolution agent for separating S-(−)-amlodipine, is expensive. Further, the methods are not readily applicable to industrial scale production because the solvent DMSO is used.
With the aim of overcoming the problems encountered in the prior art, Korean Patent No. 10-0476636 suggests a method for the resolution of S-(−)-amlodipine with L-(+)-tartaric acid. Although having an advantage over the previously mentioned patents in terms of economy, it is not suitable for application to mass production due to the use of DMSO.
Leading to the present invention, intensive and thorough research into the industrially applicable resolution of optical isomers of amlodipine, conducted by the present inventors, resulted in the finding that the use of L-(+)-tartaric acid as an optical resolution agent, with dimethylacetamide (DMAC) serving as a solvent, allows S-(−)-amlodipine to be resolved from the racemic mixture thereof at a high yield and to a satisfactory enantiomeric excess.